在经典霍奇金淋巴瘤 (cHL) 中，对免疫检查点阻断 (ICB) 的反应与特定的肿瘤微环境 (TME) 和外周血特征相关。 ICB 在结节性淋巴细胞为主的霍奇金淋巴瘤 (NLPHL) 中的作用尚未确定。为了深入了解其在 NLPHL 中的潜力，我们使用综合多组学分析比较了 HL 之间的 TME 和外周血特征。在 121 名 NLPHL 和 114 名 cHL 患者中进行的发现/验证方法强调，与 cHL 相比，NLPHL 的程序性细胞死亡 1 (PD-1) 以及 T 细胞 Ig 和 ITIM 结构域 (TIGIT) 基因表达富集了 2 倍以上。多重成像显示，与 cHL 相比，NLPHL 中 PD-1（和/或 TIGIT）CD4 T 细胞和 PD-1 CD8 T 细胞的瘤内蛋白表达显着增加。其中包括与淋巴细胞为主 (LP) 细胞和霍奇金-里德-斯滕伯格 (HRS) 细胞形成玫瑰花结的 T 细胞。在 NLPHL 中，肿瘤内 PD-1 CD4 T 细胞经常表达 TCF-1，这是 T 细胞对 ICB 反应增强的标志。 HL 之间的外周血特征也不同，与 cHL 相比，NLPHL 中的 TH1、TH2 和调节性 CD4 T 细胞中的 PD-1 TIGIT 水平较高。循环中的 PD-1 CD4 具有高水平的 TCF-1。值得注意的是，在这两种淋巴瘤中，血液中高度扩增的克隆性 TIGIT PD-1 CD4 和 TIGIT PD-1 CD8 T 细胞群也存在于 TME 中，这表明表达免疫检查点的 T 细胞在肿瘤内和肿瘤之间循环。血液隔室。在体外试验中，ICB 能够减少 LP 和 HRS 细胞周围玫瑰花结的形成，表明玫瑰花结的破坏可能是 ICB 在 HL 中的作用机制。总体而言，结果表明 NLPHL 有必要对 ICB 进行进一步评估。© 2024 作者。 《美国血液学杂志》由 Wiley periodicals LLC 出版。

In classical Hodgkin lymphoma (cHL), responsiveness to immune-checkpoint blockade (ICB) is associated with specific tumor microenvironment (TME) and peripheral blood features. The role of ICB in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is not established. To gain insights into its potential in NLPHL, we compared TME and peripheral blood signatures between HLs using an integrative multiomic analysis. A discovery/validation approach in 121 NLPHL and 114 cHL patients highlighted >2-fold enrichment in programmed cell death-1 (PD-1) and T-cell Ig and ITIM domain (TIGIT) gene expression for NLPHL versus cHL. Multiplex imaging showed marked increase in intra-tumoral protein expression of PD-1+ (and/or TIGIT+) CD4+ T-cells and PD-1+CD8+ T-cells in NLPHL compared to cHL. This included T-cells that rosetted with lymphocyte predominant (LP) and Hodgkin Reed-Sternberg (HRS) cells. In NLPHL, intra-tumoral PD-1+CD4+ T-cells frequently expressed TCF-1, a marker of heightened T-cell response to ICB. The peripheral blood signatures between HLs were also distinct, with higher levels of PD-1+TIGIT+ in TH1, TH2, and regulatory CD4+ T-cells in NLPHL versus cHL. Circulating PD-1+CD4+ had high levels of TCF-1. Notably, in both lymphomas, highly expanded populations of clonal TIGIT+PD-1+CD4+ and TIGIT+PD-1+CD8+ T-cells in the blood were also present in the TME, indicating that immune-checkpoint expressing T-cells circulated between intra-tumoral and blood compartments. In in vitro assays, ICB was capable of reducing rosette formation around LP and HRS cells, suggesting that disruption of rosetting may be a mechanism of action of ICB in HL. Overall, results indicate that further evaluation of ICB is warranted in NLPHL.© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.